CN1137685C - Non-irritation, non-sensitizing non-ototoxic otic antibacterial compositions - Google Patents
Non-irritation, non-sensitizing non-ototoxic otic antibacterial compositions Download PDFInfo
- Publication number
- CN1137685C CN1137685C CNB96190870XA CN96190870A CN1137685C CN 1137685 C CN1137685 C CN 1137685C CN B96190870X A CNB96190870X A CN B96190870XA CN 96190870 A CN96190870 A CN 96190870A CN 1137685 C CN1137685 C CN 1137685C
- Authority
- CN
- China
- Prior art keywords
- compositions
- ciprofloxacin
- weight
- percentage
- ear
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0046—Ear
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Endoscopes (AREA)
Abstract
The compositions of using in human and animal ears are non-ototoxic, non-irritating and non-sensitizing, preferably by instillation, and a method, for the treatment of otitis externa and otitis media, especially otorrhea. The compositions are aqueous based and contain ciprofloxacin and optionally hydrocortisone.
Description
Invention field
The present invention relates to treat external otitis (external ear infection) and otitis media (middle ear infection) the particularly compositions and the method for blennorrhea (otitis media of the effusion that causes with myringorupture).
Background of invention
External otitis, it comprises the inflammation of external auditory meatus part, is a kind of main common otological disease of falling ill under sweltering heat, wet climates, often the people Bi Fei swimmer's of swimming sickness rate is high more than 5 times.In the morbidity starting stage, its symptom comprises that auditory meatus is itched and pain, when time around the compressing external auditory meatus sense of tenderness is arranged, and ear-lobe affects or jaw moves.In the later stage, auditory meatus is suppurated, and audition may go down.Cases of otitis externa more than 90% is because the infection of antibacterial and fungus causes.The conventional external medication that uses, this medicated bag is drawn together antimicrobial and/or antifungal unguentum and drop.If taking place, cellulitis also can use oral antibiotic.
Otitis media for describing the term of middle ear infection, also is common disease.Being grown up particularly among the crowd, the child occupies higher sickness rate.Nearly according to estimates 95% child is in the otitis morbidity of 9 years old experience one or many, and about 15% the child that seeks medical advice is the otitis media patient.Among the child, this disease is usually followed upper respiratory tract infection, and upper respiratory tract infection can cause at pharyngotympanic tube and middle ear place and spills the liquid secretory reaction.Antibacterial and virus because of moving to middle ear through pharyngotympanic tube, and can cause eustachian tube obstruction from nose, overslaugh the ventilation and the discharging of middle ear.
Under the situation of being in a bad way, purulent exudate, toxin and endogenous antimicrobial enzyme form at middle ear, and this situation can cause the irreversible lesion of responsive neural harmony conducting tissue.It is reported with the responsive neural audition disappearance of child's 35.8% appearance of seepage otitis media.The U.S. is used for the treatment of expense with the prevention of otitis media disease every year above 1,000,000,000 dollars according to estimates.
Therapeutic Method generally comprises and systematically uses antibiotic at present; Use ear drop (U.S. food and drug administration be not approval also); With in chronicer case, go into tympanum by the myringotomy intubate tympanum can be ventilated and drain.The medication of antibiotic system generally requires the big and tangible time lag of first dosage to reach treatment level at middle ear.About the present known thing that puts drops in one's ear, people are just worrying in tympanum dispensing and are causing the infringement that material scorching and that cause infection can cause internal ear recently.It is generally acknowledged that the infringement material that is in the tympanum can cross round window membrane and enter internal ear, this round window membrane has turned out to be a kind of semipermeable membrane.The forfeiture of audition is because damage, infringement or the destructive result of interior cochlear hair cell according to recognizing.
United States Patent (USP) 4,670 has been described ciprofloxacin and its preparation in 444, incorporates it into this paper as a reference at this.Result of study has demonstrated ciprofloxacin and had partial therapeutical effect aspect ear infection.By Esposito, D ' Errico and Montanaro exist
Otorhinolaryngology head and neck surgery document116 volume 1990.5.556-559 (Arch, otolaryngo Head Neck Surg, Vol, 116, May1990, that delivers in P.556-559) is entitled as the result who has reported the clinical and bacteriological study of ciprofloxacin in suffering from chronic otitis media acute stage patient in " external and oral ciprofloxacin treatment chronic otitis media " literary composition.Drip the continuous 5-10 of saline solution days of three ciprofloxacins for twice of every day ill ear.Can see good clinical response and high percent antibacterial eradication rate and do not see ototoxicity.
By G, Stang exists
Otorhinolaryngology68 (12): reported in 653-656 (1989) (Laryngol Rhino Otol.68 (12): 653-656 (1989)) delivers is entitled as " about the topical therapeutic of the otopathy of the charrin's disease " literary composition can make by the external ear of the people due to the bacillus pyocyaneus and the very fast healing of middle ear infection with ciprofloxacin and Tutofusin topical therapeutic and do not have any complication.Eliminated the dysfunction of middle ear and internal ear, ear function is returned to normally.
People such as Garcia-Rodriguez exist
Preprint: medicine, 45 (supplement)Reported the research of " part of two kinds of schemes with the therapeutic effect of ciprofloxacin " in 1,993 40～41 pages (Preprint:Drugs 45 (Suppl) 1993.P.40～41) to ear infection.In the otic infective disorders of several types, one group with 0.5% ciprofloxacin solution, and another group was treated 7 days by the method for giving 3 drops physic liquors in per 8 hours with 0.3% ciprofloxacin solution.The gained result shows that ciprofloxacin local application treatment ear infection is effective, and seldom and slight side effect, no ototoxicity are only arranged.
At present, the ear drop of ciprofloxacin has been prepared and use under study for action although contain, and what also do not have approved can be used for the treatment of the external ciprofloxacin of otitis media disease or the appearance of other antibiotic formulations to patient by doctor's evolution.Therefore need can by patient easily be used for topical therapeutic otitis, particularly otitis media, especially blennorrhea a kind of non-stimulated, do not have irritated reaction, do not have ototoxic compositions.
Summary of the invention
The invention provides and be used for humans and animals in ear, the treatment external otitis of preferably using through drop-method and otitis media particularly no ototoxicity, the nonirritant of blennorrhea there is no anaphylactoid compositions.Said composition should arrive the infection site of middle ear by disruptive ear drum membrane, and sprawling with enough deposit thickness provides antibacterial effect on the infected area.Said composition comprises the ciprofloxacin of effective antibiotic amount; Be not subjected to the viscosity that can make compositions of pH and ionic strength affect be higher than water effective dose the nonionic viscosity intensifier and be enough to form the water of fluid composition.This viscosity intensifier is selected from the one group of chemical compound that comprises methylcellulose, polyvinyl alcohol and glycerol.
An embodiment provides all compositionss in solution of a kind of all the components.Said composition comprises the ciprofloxacin of effective antibiotic amount; Make the viscosity of compositions be higher than the methylcellulose of the effective dose of water; Prevent the potassium sorbate preservative of the effective dose of microbial contamination; Can make the sodium acetate and the acetic acid of the effective buffering dosage of pH scope between about 3-6 of compositions; Can make the scope of the effective dose that said composition sprawls on hydrophobic skin surface is the polysorbate of polysorbate 20～80; With the water that is enough to form fluid composition.
Another compositions useful that is provided by embodiment is that the latter also comprises and the tension force of compositions can be adjusted to the glycerol of about 600 milliosmolar effective doses by about 200 milliosmols, and a kind of approximate isoosmotic compositions just is provided.
Another embodiment provides the waterborne compositions that contains ciprofloxacin, and said composition comprises anti-inflammatory drug, preferred hydrocortisone.Because hydrocortisone is water insoluble, thus said composition itself be suspension it comprise: the ciprofloxacin of effective antibiotic amount; The hydrocortisone of effective antiinflammatory amount; The viscosity that can make compositions is greater than polyvinyl alcohol water and that make the effective dose of other composition suspension; For strengthening the lecithin of the effective dose that other composition suspends; The antiseptic benzylalcohol that prevents microbial contamination of effective dose; The pH scope of compositions can be buffered in the sodium acetate and the acetic acid of the effective dose between the 3-6; Can make said composition sprawl in the scope of the effective dose of hydrophobic skin surface is the polysorbate of polysorbate 20～80; Can form the water of the q.s of fluid composition.
Another effective suspension composition is that the latter also comprises and the tension force of compositions can be adjusted to the sodium chloride of about 600 milliosmolar effective doses by about 200 milliosmols, and isoosmotic approximately compositions just is provided.
In comprising the compositions of hydrocortisone, each other composition can strengthen or the resuspended buoyancy of not overslaugh insoluble composition hydrocortisone.Thereby obtain the inhomogeneity compositions of height suspension stability and height, thus, this compositions is stable and be convenient being suitable for to the user of topial treatment of disease such as otitis when long-term storage.
Also have another embodiment that a kind of compositions is provided, wherein the glycerol viscosity that increased aqueous solution composition makes its viscosity than water big.This compositions comprises: the ciprofloxacin of effective antibiotic amount; Can make the viscosity of compositions be higher than the glycerol of the effective dose of water; With the water that is enough to form fluid composition.
The present invention also provides a kind of method for the treatment of otitis, and this method comprises uses the compositions as described above of antimicrobial effective amount partly to infecting or inflamed sites.A kind of preferable methods is that said composition is splashed in the ear.If the ear drum membrane perforation, this compositions porous is to middle ear.Method with other also can be used compositions in the middle ear, and for example, by the myringotomy intubate, or by German patent DE 3,617,400. described methods can be incorporated into compositions in the middle ear by pharyngotympanic tube.When a complete ear drum membrane existed, to a certain extent, compositions also can be diffused in middle ear and the tissue around it and go.
The effective dose that is used for the compositions of in ear is preferably every day twice 1-5 and drips, and uses about 40～200 μ l promptly at every turn.
Detailed Description Of The Invention
According to the present invention, not having ototoxicity, nonirritant or do not have anaphylactoid water in ear is the substrate that contains the liquid composite of ciprofloxacin, and ciprofloxacin has higher antibacterial activity aspect the treatment otitis.The ciprofloxacin content range of effective antibiotic amount is about 0.01～1% (weight) in the aqueous solution, preferably is about 0.1～0.5% (weight).Be most preferably 0.2% (weight).
For the pollution that prevents antibacterial with a certain rational storage period is provided, the compositions that ear provided by the invention is used comprises antiseptic.Here, face the difficulty that desired antiseptic character and ciprofloxacin adapt.The antiseptic that is suitable for requires ear is not caused or not obviously causes toxicity, anaphylaxis or stimulation.Because the dissolubility of ciprofloxacin is limited in pH value approximately less than 6, so another requirement is that this antiseptic and ciprofloxacin may be dissolved in the water that exceeds common pH scope together.In the aqueous solution that contains the ciprofloxacin of percentage by weight in 0.2～1 scope, under the room temperature pH value be higher than at 5.5 o'clock and 5 ℃ of pH value 5 when above, can see having crystal settling to separate out.
Potassium sorbate, sodium benzoate and benzylalcohol are candidate's antiseptic.In containing 5 ℃ the aqueous solution that percentage by weight is about the 0.2-0.3 sodium benzoate.Can see crystal settling when pH value is less than about 4.5-5 separates out.Contain in 5 ℃ of aqueous solutions that percentage by weight is about 0.1～0.15 potassium sorbate, be lower than at 4.5 o'clock and can see crystal settling at pH value and separate out.According to the ciprofloxacin of being measured in the experiment and the water miscible pH scope of potassium sorbate, the preferred pH scope of aqueous solution that contains these materials is about 3-6, is most preferably 4.75.
Press American Pharmacopeia, the XXIII version, 1995,1681 pages of described methods are carried out antiseptic requirement experiment, find that concentration expressed in percentage by weight is 0.13%, 0.104% and 0.065% potassium sorbate; Concentration expressed in percentage by weight is 0.24% sodium benzoate; With concentration expressed in percentage by weight be that 0.9%, 0.72% and 0.45% benzylalcohol is effective antiseptic in the ciprofloxacin aqueous solution; This paper draws this method and is reference.Potassium sorbate is about 0.01～1% (weight) as the effective dose scope of the antiseptic of ciprofloxacin aqueous solution, preferably is about 0.05～0.5% (weight), most preferably is about 0.13% (weight).Benzylalcohol is about 0.1～3% (weight) as the effective dose scope of the antiseptic of the aqueous formulation that contains ciprofloxacin, preferably is about 0.1～2% (weight), most preferably is about 0.9% (weight).The dissolubility of ciprofloxacin is not subjected to the influence of benzylalcohol, and it is about 6 that the pH value of the solution of these materials can be lower than, and preferably is about 4.75.
Because the water solublity of ciprofloxacin and potassium sorbate is limited in the narrow total pH scope, so when usefulness potassium sorbate during as the antiseptic of Ciloxan, buffer agent is desirable.Citrate buffer agent can cause the ciprofloxacin precipitation, is unaccommodated.Find that acetate buffer has cushioning effect when 0.05 molar concentration.Sodium acetate and the acetic acid scope of the weight percentage of buffer preparation effectively are about 0.1～3% and 0.01～10% respectively; Preferred range is about 0.1～2% and 0.1～5%; Most preferably be about 0.4% and 0.7% respectively.
Because the dissolubility of benzylalcohol in aqueous solution do not rely on pH, and ciprofloxacin dissolves in approximately less than 6 aqueous solution at pH, so, the solution that comprises these compositions does not need buffering, and can be only with hydrochloric acid or hydrogen chloride sodium (sodium hydrochloride) pH value of solution be transferred to approximately less than 6, preferably transfer to pH and be about 4.75.Yet, can comprise for example acetate buffer of buffer agent.
For making the administration and keep at the topical application position of needs or depositing effective dose of medicine liquid from the medicine dropper of form that the ciprofloxacin liquid preparation can drip with medicine by gravity, preferably provide preferably viscosity greater than water by the material that comprises viscosity intensifier.For with ciprofloxacin and preparation in other composition adapt, preferred viscosity intensifier is not to be subjected to pH and ionic strength affect and nonionic.We find ionomer such as CVP Carbopol ETD2050 or polyacrylic acid, for example can the Carbopol trade name on market, bought and the aqueous solution of sodium carboxymethyl cellulose undesirable with the viscosity variability that ionic strength and pH change.The undesirable high concentration of other material requirement could produce the levels of viscosity that is fit to.The following examples 1 have shown the result of related substance test.All concentration are all represented from percentage by weight.
Embodiment 1
Viscosity
The CTS hydroxypropyl cellulose, 2% 7.1 hydroxypropyl emthylcelluloses, 13.7 cellulose gum, 0.5% 16.3 carboxymethyl cellulose, 1% 11.2 polyvinyl alcohol, 4% 24 polyvinylpyrrolidones, 20% 16.7 polyvinylpyrrolidone, 30% 63.7 methylcellulose, 0.5% 13.3 methylcellulose, 0.65% 49.4Carbopol, 0.28%, pH4.7 18.5Carbopol, 0.036%, pH3.9 4.7Carbopol, 0.036%, pH4.75 203
The methylcellulose of can trade name Methocel A4M buying from Dow chemical company can make the viscosity of preparation reach effective levels of viscosity at low concentration.The percentage composition scope that can effectively increase the methylcellulose of ciprofloxacin viscosity in aqueous solution is about 0.1～3%, and is preferred about 0.1～2%, is most preferably 0.6%.
For making aqueous formulation moistening and sprawl in auditory meatus and to infect or the hydrophobic skin surface of inflamed sites, surfactant is desirable.Nonionic surfactant adapts to this requirement.In test determination, find, can available from the surfactant polysorbate of american chemical industrial group commodity Tween by name particularly the polysorbate in the 20-80 scope can provide gratifying contact angle at the hydrophobic surface of politef and clean glass.Can be available from the polysorbate of other producer, the polysorbate that particularly meets American Pharmacopeia or NF standard also is fit to.Can make the weight percentage scope of the polysorbate 20～80 that the present composition sprawls at hydrophobic skin surface effectively be about 0.01～2%, preferably be about 0.05～1%, be most preferably 0.1%.Approximately in the ciprofloxacin preparation wait that to ooze be ideal situation, this can produce by adding glycerol.The weight percentage scope that can be effectively the tension force of compositions be transferred to the required glycerol of about 200～600 milliosmols is about 0.1～5%, preferably is about 0.1～2% and be most preferably 1%.
Embodiment 2
A collection of liquid composite provided by the invention is prepared by purgation.The special attachment device that uses glass container and passivation steel vessel and no visible iron ion residue such as rust.The preparation of this preparation is to carry out under no sunshine condition under sodium vapor lamp or the gold-tinted.Foaming is avoided in the transfer of solution.Adding the methylcellulose of 162.5g in being heated to the purifying waste water of about 80～90 ℃ 16364g under fusion is stirred, specifically is the Methocel A4M that Dow chemical company provides.Continue to stir up to Methocel A4M homodisperse or dissolving.This solution is cooled to about 20～25 ℃ then.Under fusion is stirred, in the purifying waste water of 500g, add 25g and meet the polysorbas20 (tween20) of American Pharmacopeia/NF standard till dissolving.This Tween20 solution is added in the Methocel A4M solution.Add glycerol 237.5g and the glacial acetic acid 63.75g that meets American Pharmacopeia/NF standard again.Dissolving meets the sodium acetate trihydrate 170g of American Pharmacopeia/NF standard in the purifying waste water of 1510g, and dissolving subsequently meets the potassium sorbate 335g of American Pharmacopeia/NF standard.This solution of gained is added in the Methocel A4M-Tween20 solution.What add in the solution of this merging that purity meets American Pharmacopeia/NF standard can be available from the ciprofloxacin 58.3g of Bayer AG.Adding water to this solution is 24500ml, with 1N hydrochloric acid or 1N sodium hydroxide pH is transferred in about 4.5-5.0 scope then, preferably transfers to about pH4.75.Add to cumulative volume with purifying waste water to the 25000ml after-filtration.A part of solution is left in the flint glass bottle of 1 type 10ml in 50 ℃ and deposited 3 months, variable color or other unsettled phenomenon do not occur.
The composition of this batch compositions is listed in the following table 1.
Table 1 composition concentration expressed in percentage by weight % Ciprofloxacin Hydrochloride 0.2332 polysorbate 20 0.10 methylcellulose 0.65 potassium sorbate 0.134 sodium acetate 0.41 acetic acid 0.7 glycerine 0.95 NaOH; 1N requirement hydrochloric acid, 1N needs water gaging 96.8228
Other several solution that contain and do not contain ciprofloxacin by described method preparation.Contain and do not contain the ciprofloxacin solution sample and in guinea pig model, show non-toxicity.
Embodiment 3
Four treated animals of every group of 5 male and Cavia porcelluss that 5 female NIH are painted the rarest, medication twice acceptance every day 10 μ of the suitable position by can being applied directly to round window membrane by the intubate of implanting l's or: the solution of forming by table 1; Form by table 1 but do not have the solution of ciprofloxacin; 0.9% sodium chloride solution; Or 10% polygynax, successive administration 30 days.The brain stem of the audition by a pretreatment (baseline) and the 14th day and the 30th day reflects estimates audition.The monitoring the weight of animals and is watched the toxic clinical symptom of animal system every day in the time of the 0th, 14 and 30 day, checks middle ear after 30 days all sidedly, and cochlea is taken out for the Histological evaluation of internal ear.By using the microphotograph mirror to measure hair cell in each cochlea down in appearance fluorescence (epifluor escent) illumination, and numeration is with acquisition cytocochleogram.
In the animal of each the group test in the first three groups, slight acoustic trauma (20～30dB) appears in few animals.Yet these animals do not have the damage of more internal ear cochlear hair cell.The damage that it is believed that audition results from middle ear, and is relevant with the fibrous tissue around the intubate of implanting the middle ear place, therefore irrelevant with the experiment material of giving.The 4th group of neomycin positive control 10% has been caused most functional anaudias and internal ear and the integrally-built damage of external ear hair cell.
Other animal does not show any tangible hearing impairment, and this result of study shows according to containing of forming of table 1 or the solution and the saline solution that do not have a ciprofloxacin all can not cause structure or functional ototoxicity.The used dosage of this test roughly be estimate to be used for the treatment of people's otopathy be present in 50 times of round window membrane place dosage.
Another embodiment of the present invention provides the no ototoxicity, the nonirritant that contain ciprofloxacin that comprise antiinflammatory glucocorticoid medicine hydrocortisone to there is no the anaphylactoid compositions that is applicable to ear.In ear, do not have ototoxicity, nonirritant or do not have the substrate of anaphylactoid water as said composition.The scope of effective antimicrobial weight percentage of ciprofloxacin is about 0.01～1% in aqueous solution, preferably is about 0.1～0.5%, is most preferably 0.2%.The weight percentage scope of the hydrocortisone of effective antiinflammatory is about 0.1～3%, preferably is about 0.1～2%, is most preferably 1%.
Because hydrocortisone has low-down water solubility, therefore comprise the hydrocortisone waterborne suspension that hydrochloric ciprofloxacin is made in the hydrocortisone requirement.Be the convenient person of using, Pharmaceutical composition preferably should have suitable storage period, is preferably 2 years.Therefore any insoluble composition all should be in suspended state, or passes through suitable agitato vase resuspension easily.Whole compositions homodisperse and high degree of dispersion in container make can all even multiple dosage to take out and be used for the host.
In one of principal element that is consideration owing to heavy dispersibility aspect the evaluation suspension qualification, again because of formed precipitum should easily scatter by suitable jolting so that form uniform system, therefore, the mensuration of settling volume and its heavy dispersive easiness has formed as by L, Lochman, H, A, Leiberman, J, L, Kanig,
The theory and practice of industrial pharmacy(Theory andpractice of Industrial Pharmacy) second edition, 159,180 pages of the above two kinds of modal basic evaluation methodologys.Adopt the method for being advised in this book to measure the material that the resuspended buoyancy of examination compositions and sedimentation rate and discovery can increase the suspension of the hydrocortisone in the aqueous matrix.By making bottle seen sedimentation after standing over night that composition sample is housed disperse the needed turnover number that is referred to as to clash into to estimate the resuspended buoyancy of examination composition and compositions again.With standing over night after the graduated cylinder jolting of the high suspension sample of 20mm is housed, estimate sedimentation rate by the height (millimeter) of observing the settling leg that in the high suspension of 20mm, occurs.Settled height is big more favourable more, shows less separation, and supernatant is less and sedimentation is not too tight.
For making the ciprofloxacin preparation can also can keep or deposit the medicinal liquid of effective dose from medicine dropper outflow administration with the form of drop in selected topical application zone by gravity.The Bees Wax that hydrocortisone is played suspension effect also is desirable.Increase to ability about the ability of hydride suspension cortisone in the aqueous solution of ciprofloxacin with the viscosity of compositions, estimated a large amount of reagent by above-mentioned method greater than the viscosity of water.The dissolubility that be to be fit to ciprofloxacin, such reagent preferably nonionic and be not subjected to pH and ionic strength affect.The aqueous solution that it is found that ionomer such as Carbopol and sodium carboxymethyl cellulose has undesirable viscosity variability that changes with ionic strength and pH.The undesirable high concentration of other material requirement just produces suitable levels of viscosity.Methylcellulose can make preparation produce effective levels of viscosity at low concentration, but discovery is invalid aspect the hydride suspension cortisone.
In the above-mentioned test of carrying out, the concentration expressed in percentage by weight of polyvinyl alcohol is about and can produces suitable viscosity at 2% o'clock and can demonstrate higher suspension ability to hydrocortisone in aqueous formulation, and the embodiment of polyvinyl alcohol that uses 99% hydrolysis is as follows.
Embodiment 4
Heavy dispersive bump several 4 after the standing over night
Original height of specimen, mm 50
Sedimentary column height after the standing over night, mm 9
Compare with the compositions that contains consoluet polyvinyl alcohol, contain less bump number of the compositions display of partly soluble polyvinyl alcohol and bigger settling volume.Yet because the variability of expection and occur in the variation of the dissolving quantity under the variations in temperature condition of the expectation in the storage, the compositions that contains consoluet polyvinyl alcohol is preferred.Degree of hydrolysis is that 85% polyvinyl alcohol can play suspension effect to hydrocortisone effectively.Yet that is measured has moderate viscosity, and degree of hydrolysis is that 99% polyvinyl alcohol has better suspension effect to hydrocortisone.Such material can have been bought commodity Airvol 125 by name from Air product and chemicals company limited (Air Products and Chemicals Inc).The weight percentage scope that can increase the viscosity of the waterborne compositions that contains ciprofloxacin effectively and make hydrocortisone be suspended in the polyvinyl alcohol in this waterborne compositions effectively is about 0.1～10%, preferably is about 1～5%, is most preferably 2%.
In containing the aqueous formulation of ciprofloxacin and other composition, reach the adding that concentration expressed in percentage by weight is about 0.15% lecithin and can strengthen the suspension effect of polyvinyl alcohol hydrocortisone.In the suspension test, estimated the lecithin of two kinds of grades.A kind of is complete hydrogenant soybean lecithin.It comprises 90% phosphatidylcholine, can buy from U.S. lecithin company, and commodity are called Phospholipon 90H, and this lecithin is effective.A kind of soybean lecithin that comprises 75% phosphatidylcholine can have been bought from Vernon Walden company limited, and commodity are called Lipoid-S75, also are effective.The weight percentage scope that can increase the required lecithin of suspension of hydrocortisone in the waterborne compositions that contains ciprofloxacin and polyvinyl alcohol effectively is about 0.01～5%, preferably is about 0.01～2%, is most preferably 0.15%.
For the pollution that prevents antibacterial with a certain rational storage period is provided, it is desirable adding antiseptic at ear in pharmaceutical preparation.Here face the character of desired antiseptic and the difficulty that ciprofloxacin adapts.The antiseptic that is suitable for requires not produce or seldom produce ototoxicity, anaphylaxis or in the zest of auditory meatus or middle ear.Another requirement is that this antiseptic and ciprofloxacin may be dissolved in the water in common pH scope together.Because the dissolubility of the ciprofloxacin of being measured is limited in the narrow pH scope.Contain in the aqueous solution that percentage by weight is about 0.2～1% ciprofloxacin, under the room temperature pH 5.5 when above and 5 ℃ of pH be 5 when above, can observe crystal settling and separate out.
Find that in suspension test concentration expressed in percentage by weight is about the suspension that 0.9% benzylalcohol can strengthen or not subdue hydrocortisone in the preparation.Press American Pharmacopeia, the XXIII version, the methods (incorporating this piece of writing into as a reference at this) that 1995,1681 pages described carries out antiseptic requirement test are measured discovery, and concentration expressed in percentage by weight is that 0.9,0.72 and 0.45% benzylalcohol has antisepsis in the ciprofloxacin aqueous formulation.In containing the aqueous formulation of ciprofloxacin, effectively the weight percentage scope of antiseptical benzylalcohol is about 0.1～3%, preferably is about 0.1～2%, is most preferably 0.9%.Because the dissolubility of ciprofloxacin is not subjected to the influence of benzylalcohol, therefore, the pH value of solution of these materials can preferably be about 4.75 less than 6.
Although unnecessary, it is preferred comprising buffer agent.It is found that acetate buffer has buffering effect when 0.05 molar concentration.In order to strengthen or do not weaken the suspending power of hydrocortisone in preparation, also the Dichlorodiphenyl Acetate salt buffer agent is measured.The scope that sodium acetate and acetic acid can be effectively carry out buffered weight percentage to preparation is about 0.1～3% and 0.01～10% respectively; Preferably be about 0.1～2% and 0.1～5% respectively, most preferably be about 0.4% and 0.7% respectively.
For make the aqueous formulation moistening and sprawl in auditory meatus infect or the hydrophobic skin surface at the position of inflammation on, surfactant is desirable.Nonionic surfactant is at this brief description.In test determination, find, be referred to as polysorbate within 20 to 80 of the surfactant of polysorbate, particularly scope (can be, Inc. has bought, commodity are called Tween) from ICI Americas.On the hydrophobic surface of politef and clean glass, can provide gratifying contact angle.Can particularly meet also being suitable for of American Pharmacopeia or NF standard available from the polysorbate of other producer.Measure to find that concentration expressed in percentage by weight is that 0.1% Tween20 and Tween80 can increase or not weaken the suspendability of hydrocortisone in the aqueous formulation that contains ciprofloxacin and polyvinyl alcohol effectively.The present composition is sprawled effectively in the required scope of hydrophobic skin surface be about 0.01～2%, preferably be about 0.05～1%, most preferably be 1% in the scope of the weight percentage of 20～80 polysorbate.
It is desirable being oozed by the approximate grade that adds the sodium chloride generation in the ciprofloxacin preparation.Measure to find that in the aqueous formulation that contains ciprofloxacin and other composition, concentration expressed in percentage by weight is about 0.9% sodium chloride and can strengthens or not weaken hydrocortisone effectively and contain suspending power in ciprofloxacin and other composition aqueous formulation at this.Can be effectively the tension force of compositions be about 0.1～5% by the weight percentage scope that about 200 milliosmols are adjusted to required sodium chloride in the 600 milliosmol scopes, preferably be about 0.1～2%, be most preferably 0.9%.
Embodiment 5
Prepare as follows by a collection of compositions provided by the invention.The special attachment device that uses glass container and passivation steel vessel and no visible iron ion residue such as rust.The preparation of this preparation is to carry out under no sunshine condition under sodium vapour lamp or the gold-tinted.Foaming is avoided in the transfer of solution.Purifying waste water of 15255g is heated to 90～95 ℃, under nitrogen environment, it is cooled to 20～25 ℃ then, be suitable for premixing, additional middle use of flushing and final volume afterwards.In being heated to the purifying waste water of about 90～95 ℃ 15255g, add polyvinyl alcohol 500g under stirring mixing, until dissolving fully.Mixing under the stirring, in gained solution, adding phospolipon 90H (lecithin) 36.5g, until disperseing fully.When nitrogen is passed into the head space of the container of containing this solution, begin solution is cooled to 40～50 ℃.Along with the benzylalcohol 25g that adding meets American Pharmacopeia/NF standard in this solution is stirred in fusion, stir till dissolving.Continue to feed nitrogen and be cooled to 20～25 ℃.Sneak into the glacial acetic acid 63.75g that meets American Pharmacopeia/NF standard.In another container, will meet the sodium chloride of 225g of American Pharmacopeia/NF standard and the sodium acetate trihydrate of 170g and be dissolved in the purifying waste water of 1525g, then this solution is added in the main proportion liquid.The polysorbate 25g that will meet American Pharmacopeia/NF standard is dissolved in during 2743g in container separately purifies waste water.Add the micronized hydrocortisone that 250g meets American Pharmacopeia/NF standard down with the fusion stirring, until moistening fully and dispersion.Feed under the condition of nitrogen to main proportion liquid add and dissolving purity meet American Pharmacopeia/NF standard be equivalent to weight percentage be 0.2% ciprofloxacin ciprofloxacin 58.3g (in addition, also ciprofloxacin and glacial acetic acid can be dissolved in advance together with sodium acetate trihydrate in the water of about 3000g, be added to then in the main proportion liquid).The pre-composition of hydrocortisone is added to back mixing in the main batching.Add purify waste water to batch volume be 24500ml, transfer to pH4.75 with the hydrochloric acid of IN or the sodium hydroxide of N.Adding then purifies waste water to batch volume reaches 25000ml.This batch compositions composition is listed in the following table 2.
Table 2 constituent concentration; % by weight Ciprofloxacin Hydrochloride 0.2332 hydrocortisone 1 polysorbate 20 0.10 polyvinyl alcohol 2.0phospholipon 90H 0.15 benzylalcohol 0.9 acetic acid 0.7 sodium acetate 0.41 sodium chloride 0.9 NaOH; 1N requirement hydrochloric acid, 1N needs water gaging 93.6068
Carry out the dispersibility and the settling test of the composition sample listed above by above-mentioned method of giving, its result shows in the following embodiments.
Embodiment 6
Heavy dispersive bump several 3 after the standing over night
Original height of specimen, mm 50
Settling height after the standing over night, mm 11
This batch sample was stored 1 month at 5 ℃ and 50 ℃.Other sample stands the freezing and thaw cycles in a week.No matter the result is settling volume or its redispersibility in any sample, does not all significantly change.By above-mentioned composition sample dispersibility and the settling test of listing above carrying out to method, its result shows in the following embodiments sample after 50 ℃ are deposited one month.
Embodiment 7
Heavy dispersive bump is counted 3-4 after the standing over night
The height of original sample, mm 50
Settling height after the standing over night, mm 9-11
Other batch compositions that table 2 forms that has that contains or do not have a ciprofloxacin prepares by described method.The formulation samples that contains or do not contain ciprofloxacin like this shows no ototoxicity in the Cavia porcellus animal model.
Embodiment 8
Three treated animals of every group of 5 male and Cavia porcelluss that 5 female NIH are painted the rarest, by from implanting the medication that intubate is applied directly to the suitable position of round window membrane, every day two this accept 10 μ l's or by the compositions of table 2; By table 2 but there is not the compositions of ciprofloxacin; Or by table 2 but do not have the compositions of ciprofloxacin and hydrocortisone, successive administration 30 days.ASR by a pretreatment (baseline) and the 14th day and the 30th day is estimated audition.At the 0th, 14 day and 30 days monitoring the weight of animals, and observe the toxic clinical indication of animal system every day, after 30 days the animal middle ear are checked all sidedly, for the Histological evaluation that carries out internal ear takes out interior cochlea.By using the microphotograph mirror to measure hair cell in each cochlea under the appearance fluorescent illumination, and numeration is to obtain cytocochleogram.
More weak hearing impairment (20-40dB) appears in an animal in animal in first group and second group.Yet these animals do not have the damage of more internal ear cochlear hair cell.Think the damage cause middle ear of audition, relevant with the fibrous tissue around the intubate of implanting the middle ear place.Thereby it is irrelevant with the experiment material that gives.
Any tangible hearing impairment does not appear in other animal in this experiment.This result of study shows that none can cause structure or functional ototoxicity in the applied compositions.
Another embodiment of the present invention provides a kind of do not have ototoxicity, nonirritant and the no anaphylactoid otic solution compositions that contains ciprofloxacin, and wherein glycerol has increased this viscosity in aqueous solution and makes its viscosity greater than water.Concentration expressed in percentage by weight is about 50～95% glycerol can provide the range of viscosities that is suitable for that is about 10～200 centistokes.Preferred glycerol concentration expressed in percentage by weight scope is about 70～90%, most preferably is 87%.The concentration expressed in percentage by weight scope of the antimicrobial ciprofloxacin effectively in such aqueous solution is about 0.01～1%, preferably is about 0.1～0.5%, is most preferably 0.2%.
Can add buffer agent a kind of pH scope is provided for keeping the dissolubility of ciprofloxacin in compositions.The pH scope is fit between 3-6.For making sodium acetate and acetic acid be about 0.01～2% and 0.01～5% respectively to the weight percentage scope that compositions plays required sodium acetate of cushioning effect and acetic acid effectively, preferably be about 0.02～1% and 0.1～2% respectively, most preferably be about 0.05 and 0.16% respectively.
Embodiment 9
According to the present embodiment, it is 0.2% ciprofloxacin, 87.0% glycerol, 0.05% sodium acetate, 0.16% acetic acid that preparation contains weight percentage, and remaining is a kind of solution of water.Find that after measured said composition reasonably is being enough to microbial contamination resistance in the storage-life.Yet the antiseptic that Xiangshan potassium sorbate or benzylalcohol are such for increasing the protection effect, can be included in the compositions.In view of the result of the test of carrying out in Cavia porcellus with other the compositions that contains this solution component, people's middle ear and external ear used in this solution part, no ototoxicity, the irritated reaction of nonirritant and nothing.
Above-mentioned embodiment and embodiment are illustrative, are not the restrictions to invention.Be also included among the present invention with the meaning of claim equivalence and the change in the scope.
Claims (7)
1. be used for the treatment of mammiferous no ototoxic waterborne compositions, it comprises:
(a) percentage by weight is the ciprofloxacin or its pharmaceutically acceptable salt that exist with aqueous solution of 0.01～1.0% antimicrobial effective amount;
(b) percentage by weight is 0.1～3.0% the hydrocortisone or its pharmaceutically acceptable salt that exist with aqueous dispersions as the anti-inflammatory drug effective dose; With
(c) percentage by weight be 0.1～10.0% effective dose can make hydrocortisone be suspended in degree of hydrolysis in the solution to be at least 85% polyvinyl alcohol.
2. the compositions of claim 1 also comprises percentage by weight and is 0.01～5.0% lecithin.
3. the compositions of claim 1, further comprising the percentage by weight that is present in the compositions is the benzylalcohol of 0.1-3%.
4. the compositions of claim 1 further comprises the acetate buffer of 0.05 molar concentration.
5. the compositions of claim 1 further comprises percentage by weight and is 0.01～2% polysorbate.
6. the compositions of claim 1 further comprises percentage by weight and is 0.1～5% sodium chloride.
7. the compositions of claim 1 further comprises the polyvinyl alcohol of at least 99% hydrolysis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46504895A | 1995-06-06 | 1995-06-06 | |
| US08/465,048 | 1995-06-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1160999A CN1160999A (en) | 1997-10-01 |
| CN1137685C true CN1137685C (en) | 2004-02-11 |
Family
ID=23846298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB96190870XA Expired - Lifetime CN1137685C (en) | 1995-06-06 | 1996-06-05 | Non-irritation, non-sensitizing non-ototoxic otic antibacterial compositions |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5965549A (en) |
| EP (1) | EP0782448B1 (en) |
| CN (1) | CN1137685C (en) |
| AT (1) | ATE214931T1 (en) |
| AU (1) | AU708540B2 (en) |
| CA (1) | CA2199294C (en) |
| DE (1) | DE69620136T2 (en) |
| DK (1) | DK0782448T3 (en) |
| ES (1) | ES2173287T3 (en) |
| HK (1) | HK1002552A1 (en) |
| IL (1) | IL120317A (en) |
| MX (1) | MX9701731A (en) |
| NZ (1) | NZ309624A (en) |
| PT (1) | PT782448E (en) |
| TW (1) | TW464499B (en) |
| WO (1) | WO1996039146A1 (en) |
| ZA (1) | ZA964653B (en) |
Families Citing this family (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6395746B1 (en) * | 1998-09-30 | 2002-05-28 | Alcon Manufacturing, Ltd. | Methods of treating ophthalmic, otic and nasal infections and attendant inflammation |
| US6509327B1 (en) | 1998-09-30 | 2003-01-21 | Alcon Manufacturing, Ltd. | Compositions and methods for treating otic, ophthalmic and nasal infections |
| US6716830B2 (en) | 1998-09-30 | 2004-04-06 | Alcon, Inc. | Ophthalmic antibiotic compositions containing moxifloxacin |
| EP1117406A1 (en) * | 1998-09-30 | 2001-07-25 | Alcon Laboratories, Inc. | Antibiotic compositions for treatment of the eye, ear and nose |
| AR020661A1 (en) * | 1998-09-30 | 2002-05-22 | Alcon Lab Inc | A PHARMACEUTICAL COMPOSITION TOPICA OFTALMICA, OTICA OR NASAL AND THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| US6500360B2 (en) * | 1999-06-18 | 2002-12-31 | Bernard Bendiner | Sorbic acid and/or its derivatives, such as potassium sorbate, as a preventative for rust, corrosion and scale on metal surfaces |
| US7064132B2 (en) * | 1999-11-28 | 2006-06-20 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis external |
| US6156294A (en) | 1999-11-28 | 2000-12-05 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
| ES2160090B1 (en) * | 2000-03-16 | 2002-07-01 | Vita Invest Sa | Set of aqueous cyprofloxacin otitis pharmaceuticals comprises single dose products treating perforated eardrums by dropwise administration |
| US6462033B2 (en) | 2000-07-26 | 2002-10-08 | Alcon Universal Ltd. | Process for manufacturing compositions containing ciprofloxacin and hydrocortisone |
| AU2001291219A1 (en) | 2000-09-25 | 2002-04-08 | Bayer Healthcare Llc | Otic microbial combinations for treatment of animals with ruptured tympanic membrane |
| ES2250739T3 (en) | 2001-09-21 | 2006-04-16 | Alcon, Inc. | METHOD FOR TREATING MID EAR INFECTIONS. |
| US7718189B2 (en) | 2002-10-29 | 2010-05-18 | Transave, Inc. | Sustained release of antiinfectives |
| US20040101506A1 (en) * | 2002-11-25 | 2004-05-27 | Fust Charles A. | Composition for the prevention and treatment of inflammation of the ear |
| US7842791B2 (en) * | 2002-12-19 | 2010-11-30 | Nancy Jean Britten | Dispersible pharmaceutical compositions |
| US20040214753A1 (en) * | 2003-03-20 | 2004-10-28 | Britten Nancy Jean | Dispersible pharmaceutical composition for treatment of mastitis and otic disorders |
| US20050004098A1 (en) * | 2003-03-20 | 2005-01-06 | Britten Nancy Jean | Dispersible formulation of an anti-inflammatory agent |
| US20050009931A1 (en) * | 2003-03-20 | 2005-01-13 | Britten Nancy Jean | Dispersible pharmaceutical composition for treatment of mastitis and otic disorders |
| MXPA05009978A (en) * | 2003-03-20 | 2005-11-04 | Pharmacia Corp | Dispersible formulation of an anti-inflammatory agent. |
| KR100780983B1 (en) * | 2003-07-31 | 2007-11-30 | 파마시아 앤드 업존 캄파니 엘엘씨 | Dispersible formulation of an anti-inflammatory agent |
| KR100807414B1 (en) * | 2003-07-31 | 2008-02-25 | 파마시아 앤드 업존 캄파니 엘엘씨 | Dispersible pharmaceutical composition for treatment of mastitis and otic disorders |
| ES2552936T3 (en) | 2003-12-12 | 2015-12-03 | Otic Pharma Ltd. | Compositions for the treatment of disorders in the ear and methods for their use |
| US8940321B2 (en) | 2003-12-12 | 2015-01-27 | Otic Pharma Ltd. | Compositions for treatment of ear disorders and methods of use thereof |
| US20060019987A1 (en) * | 2004-07-23 | 2006-01-26 | Fust Charles A | Methods and compositions for inhibiting, destroying, and/or inactivating viruses |
| AU2006322076C1 (en) | 2005-12-08 | 2013-11-14 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections |
| US20100196455A1 (en) | 2007-05-04 | 2010-08-05 | Transave, Inc. | Compositions of Multicationic Drugs for Reducing Interactions with Polyanionic Biomolecules and Methods of Use Thereof |
| US9114081B2 (en) | 2007-05-07 | 2015-08-25 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
| US9119783B2 (en) | 2007-05-07 | 2015-09-01 | Insmed Incorporated | Method of treating pulmonary disorders with liposomal amikacin formulations |
| UA111147C2 (en) * | 2009-11-11 | 2016-04-11 | Байєр Б.В. | METHODS AND COMPOSITIONS FOR THE TREATMENT OR PREVENTION OF EXTERNAL OTITIS |
| DK2366408T3 (en) | 2010-03-01 | 2012-10-22 | Salvat Lab Sa | Aqueous clear solutions of fluocinolone acetonide to treat inflammation of the ear |
| HU227743B1 (en) * | 2011-07-22 | 2012-02-28 | Debreceni Egyetem | Eardrop composition and process for producing this |
| MX2014006803A (en) * | 2011-12-09 | 2014-07-09 | Lupin Ltd | Topical pharmaceutical compositions of anti-microbial agents and anti-inflammatory agents. |
| MX2015006681A (en) | 2012-11-29 | 2016-04-06 | Insmed Inc | Stabilized vancomycin formulations. |
| ES2981634T3 (en) | 2014-05-15 | 2024-10-09 | Insmed Incorporated | Methods for treating nontuberculous pulmonary mycobacterial infections |
| US9393243B1 (en) | 2015-07-14 | 2016-07-19 | Nilesh Parikh | Topical Ciprofloxacin compositions |
| EP3773505A4 (en) | 2018-03-30 | 2021-12-22 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4025620A (en) * | 1975-10-22 | 1977-05-24 | Leo Pharmaceutical Products Ltd., A/S | Treatment of canine otitis and composition therefor |
| US4670444B1 (en) * | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
| DE3471639D1 (en) * | 1983-03-31 | 1988-07-07 | Payne Packaging Ltd | Improvements in or relating to tapes |
| DE3537761A1 (en) * | 1985-10-24 | 1987-04-30 | Bayer Ag | INFUSION SOLUTIONS OF 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7- (1-PIPERAZINYL) -QUINOLINE-3-CARBONIC ACID |
| DE3704907A1 (en) * | 1987-02-17 | 1988-08-25 | Bayer Ag | TOPICALLY APPLICABLE PREPARATIONS OF GYRASE INHIBITORS IN COMBINATION WITH CORTICOSTEROIDS |
| DE3902079A1 (en) * | 1988-04-15 | 1989-10-26 | Bayer Ag | IN THE. INJECTION FORMS OF GYRASE INHIBITORS |
| US5061729A (en) * | 1988-06-08 | 1991-10-29 | Biogal Gyogyszergyar | Pharmaceutical composition and process for preparing the same |
| US5271939A (en) * | 1988-10-03 | 1993-12-21 | Alcon Laboratories, Inc. | Pharmaceutical compositions and methods of treatment to prevent and treat corneal scar formation produced by laser irradiation |
| US5260073A (en) * | 1990-05-21 | 1993-11-09 | Norwich Eaton Pharmaceuticals, Inc. | Use of phenylpropanolamine as a mucus secretogogue in the upper airways |
| AU5599594A (en) * | 1992-11-16 | 1994-06-08 | Ciba-Geigy Ag | Polyvinyl alcohol/borate ophthalmic drug delivery system |
| US5422116A (en) * | 1994-02-18 | 1995-06-06 | Ciba-Geigy Corporation | Liquid ophthalmic sustained release delivery system |
| ES2088742B1 (en) * | 1994-06-29 | 1997-03-16 | Salvat Lab Sa | ANTIBIOTIC COMPOSITION OF OTIC APPLICATION. |
-
1996
- 1996-06-05 NZ NZ309624A patent/NZ309624A/en not_active IP Right Cessation
- 1996-06-05 ZA ZA964653A patent/ZA964653B/en unknown
- 1996-06-05 CN CNB96190870XA patent/CN1137685C/en not_active Expired - Lifetime
- 1996-06-05 DE DE69620136T patent/DE69620136T2/en not_active Expired - Lifetime
- 1996-06-05 CA CA002199294A patent/CA2199294C/en not_active Expired - Lifetime
- 1996-06-05 ES ES96917172T patent/ES2173287T3/en not_active Expired - Lifetime
- 1996-06-05 IL IL12031796A patent/IL120317A/en not_active IP Right Cessation
- 1996-06-05 EP EP96917172A patent/EP0782448B1/en not_active Expired - Lifetime
- 1996-06-05 WO PCT/US1996/008864 patent/WO1996039146A1/en active IP Right Grant
- 1996-06-05 PT PT96917172T patent/PT782448E/en unknown
- 1996-06-05 AU AU59840/96A patent/AU708540B2/en not_active Expired
- 1996-06-05 DK DK96917172T patent/DK0782448T3/en active
- 1996-06-05 MX MX9701731A patent/MX9701731A/en unknown
- 1996-06-05 AT AT96917172T patent/ATE214931T1/en active
- 1996-06-06 TW TW085106748A patent/TW464499B/en not_active IP Right Cessation
-
1997
- 1997-02-18 US US08/801,891 patent/US5965549A/en not_active Expired - Lifetime
-
1998
- 1998-03-02 HK HK98101616A patent/HK1002552A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IL120317A (en) | 2000-08-13 |
| DE69620136T2 (en) | 2002-08-01 |
| AU708540B2 (en) | 1999-08-05 |
| US5965549A (en) | 1999-10-12 |
| EP0782448B1 (en) | 2002-03-27 |
| CN1160999A (en) | 1997-10-01 |
| TW464499B (en) | 2001-11-21 |
| ES2173287T3 (en) | 2002-10-16 |
| EP0782448A1 (en) | 1997-07-09 |
| NZ309624A (en) | 1999-04-29 |
| DE69620136D1 (en) | 2002-05-02 |
| PT782448E (en) | 2002-07-31 |
| WO1996039146A1 (en) | 1996-12-12 |
| HK1002552A1 (en) | 1998-09-04 |
| CA2199294C (en) | 2000-09-19 |
| DK0782448T3 (en) | 2002-07-08 |
| ZA964653B (en) | 1996-12-12 |
| EP0782448A4 (en) | 1998-05-20 |
| MX9701731A (en) | 1997-10-31 |
| ATE214931T1 (en) | 2002-04-15 |
| IL120317A0 (en) | 1998-06-15 |
| CA2199294A1 (en) | 1996-12-12 |
| AU5984096A (en) | 1996-12-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1137685C (en) | Non-irritation, non-sensitizing non-ototoxic otic antibacterial compositions | |
| CN102079794B (en) | Mucoadhesive xyloglucan-containing formulations useful in medical devices and in pharmaceutical formulations | |
| US20180243335A1 (en) | Methods and compositions for treating inflammatory disorders | |
| US10201519B2 (en) | Stabilized pediatric suspension of carisbamate | |
| EP1754491B1 (en) | Ophthalmic percutaneously absorbed preparation containing muscarinic receptor agonist | |
| US20090191288A1 (en) | Composition to Treat Herpes, Pseudomonas, Staph, Hepatitis and Other Infectious Diseases | |
| DK2387389T3 (en) | Composition for oral transmucosal administration of analgesic or antispasmodic molecules | |
| PT1408911E (en) | Sustained-release therapeutic bioadhesive systems | |
| JP2018065852A (en) | Novel iodophor composition and methods of use | |
| CN107837276A (en) | The pharmaceutical composition being locally administered | |
| CN107865966A (en) | The compound amino glycoside pharmaceutical composition being locally administered | |
| CN101484138A (en) | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same | |
| CN107837275A (en) | The pharmaceutical composition being locally administered | |
| CN101987109A (en) | Ophthalmic composition containing povidone iodine and cyclodextrin included glucocorticoid | |
| EA011215B1 (en) | Therapeutic system comprising amoxicillin and clavulanic acid | |
| WO2017151664A1 (en) | Pharmaceutical compositions for fluoroquinolone drug delivery | |
| CN104224802B (en) | A kind of moxifloxacin hydrochloride auristilla and preparation method thereof | |
| CN101028516B (en) | Medicine preparation for oral cavity | |
| CN111529491B (en) | Quick-acting safe ticagrelor oral spray and preparation method thereof | |
| CN107260731A (en) | One kind is used to prevent and treat dog duct inflammation, dermopathic pharmaceutical composition and its application | |
| CN101138586A (en) | Riboflavin natural indigo mouth ulcer paster | |
| Qabajeh | Preparation and Characterization of a Novel Chitoson/Soluplus® Fast Oral Dissolving Film | |
| rights are reserved by Himanshu | A Comprehensive Review on Pharmaceutical Liquid Dosage Form | |
| Kinagi | Design And Evaluation Of Buccal Tablets Of Granisetron Hydrochloride | |
| Alase | Sustained Ophthalmic Delivery Of Gatifloxacin From In Situ Gelling System |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: BAYER CORP., USA TO: BAYER AG |
|
| CP03 | Change of name, title or address |
Address after: Germany Leverkusen Applicant after: Bayer AG Address before: American Pennsylvania Applicant before: BAYER Corp. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: BAYER SCHERING PHARMA AG Free format text: FORMER OWNER: BAYER AG Effective date: 20091016 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20091016 Address after: Berlin Patentee after: BAYER SCHERING PHARMA AG Address before: The Federal Republic of Germany Leverkusen Patentee before: Bayer AG |
|
| ASS | Succession or assignment of patent right |
Owner name: BAYER INTELLECTUAL PROPERTY GMBH Free format text: FORMER OWNER: BAYER PHARMACEUTICALS AG Effective date: 20130326 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: BAYER PHARMACEUTICALS AG Free format text: FORMER NAME: BAYER SCHERING PHARMA AG |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Berlin Patentee after: BAYER PHARMA AG Address before: Berlin Patentee before: Bayer Schering Pharma AG |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130326 Address after: German Monheim Patentee after: BAYER INTELLECTUAL PROPERTY GmbH Address before: Berlin Patentee before: BAYER PHARMA AG |
|
| CX01 | Expiry of patent term |
Granted publication date: 20040211 |
|
| EXPY | Termination of patent right or utility model |